NEJM 29 May 2014 Vol 370
2071 This week’s New England Journal is dominated by three papers on idiopathic pulmonary fibrosis. The editorial on them begins “I suspect that many of my patients have picked up on more than a hint of frustration in my voice when I tell them that the cause of their shortness of breath is idiopathic pulmonary fibrosis.” Well, yes, I expect they will share your frustration, especially when you tell them that they are likely to be dead within five years. So what hope do the new interventions bring? Really only a small glimmer. Nintedanib is an intracellular inhibitor that targets multiple tyrosine kinases, and these are thought to play a key role in sustaining the abnormal healing process which keeps producing fibrosis in the lungs. In this year long phase 3 trial, patients who took nintedanib felt no different from those on placebo, except that they had a little more diarrhoea. However, their forced vital capacity declined less and they took longer to experience their first acute exacerbation.
2083 It was a very similar story with this year long phase 3 trial of pirfenidone, an oral antifibrotic agent. It slowed progression as measured by FVC but this trial alone did not show a mortality benefit within its timescale. Combined with other pirfenidone studies, however, it seems the drug does have a significant effect on all cause mortality and on mortality from pulmonary fibrosis.
2093 Finally a 60 week trial of acetylcysteine, a long used mucolytic agent. This simply did nothing more than placebo.
2102 “Thymic stromal lymphopoietin (TSLP) is an epithelial-cell–derived cytokine that is produced in response to proinflammatory stimuli and drives allergic inflammatory responses through its activity on a number of innate immune cells, including dendritic cells, mast cells, and CD34+ progenitor cells.” When you read a sentence like this in the introduction of a paper, you know to be on your guard. Most drugs that work have a mechanistic logic; most drugs that do not work, including some that kill, have a mechanistic logic. Here, at least, the makers of AMG 157, a TSLP antibody, are honest in their claims for their proof of concept trial: “Whether anti-TSLP therapeutics will have clinical value cannot be determined from these data.” The data show that treatment with AMG 157 reduced allergen-induced bronchoconstriction and indexes of airway inflammation before and after allergen challenge. So this is a space worth watching, and a rather unexpected one, as the editorial explains.
2110 The world has been waiting a long time for an effective cholera vaccine. Getting cholera itself is highly immunogenic, but decidedly unpleasant: most of those who died in the Haiti outbreak did so within 12 hours of the start of diarrhoea and vomiting, simply for lack of fluid replacement. Achieving immunogenicity without toxicity now seems to have been achieved with two vaccines, one of which is called Shanchol. This is much cheaper and easier to store than its rival, Dukoral. Here is a description of its use in a cholera outbreak in Guinea in 2012, funded by Médecins sans Frontières. Vaccination with two complete doses was associated with significant protection against cholera (effectiveness, 86.6%; 95% confidence interval, 56.7 to 95.8; P=0.001).
JAMA Intern Med May 2014
OL MsFLASH has sites in Boston, Philadelphia, and Seattle. It is not in fact a chain of table-dancing bars, but a highly respectable research network investigating treatment for menopausal vasomotor symptoms (VMS). It has long been known that these respond well to oestrogen replacement (referred to here as ET, estrogen therapy), but often return as soon as this is stopped. Now that ET has fallen into disfavour, doctors often prescribe a variety of serotonin reuptake inhibitors instead. My worry is that these can cause even worse discontinuation symptoms in many people. A particularly “reboundy” drug in my experience is venlafaxine, which also blocks noradrenaline uptake, and may well have worse long term cardiovascular safety than hormone replacement therapy. In this eight week trial, participants were randomized to double blind treatment with low dose oral 17β-estradiol (0.5 mg/d) (n = 97), low dose venlafaxine hydrochloride extended release (75 mg/d) (n = 96), or placebo (n = 146). In those two months the two active treatments reduced flushes/flashes by a similar amount. More women preferred the oestrogen. So how long should they take it for? And what happens if they come off? Come on, MsFLASH, show us your stuff.
OL Although I am an inveterate generalist, if asked to put down my “special interests” I tend to say end of care for heart failure, and shared decision making. I would like to make some swan song contributions to both, if I can keep the necessary complex ideas together in my head for long enough. A critical issue in both fields is preference stability. For anyone who is interested, here is a terrific systematic review of studies of stability in end of life preferences. “Preference stability was generally greater among inpatients and seriously ill outpatients than among older adults without serious illnesses (P < .002). Patients with higher education and who had engaged in advance care planning had greater preference stability, and preferences to forgo therapies were generally more stable than preferences to receive therapies.” But assume nothing—in dying even more than in living, people have a right to be themselves and to change their minds. Be with them and support them, as you would wish to be supported yourself.
JAMA 28 May 2014 Vol 311
2074 Hey midwives and GPs: if you can’t persuade a pregnant mum to give up smoking, give her vitamin C. That’s the unexpected conclusion of a trial, which randomized 179 pregnant smokers to 500mg of ascorbic acid daily or placebo. “Supplemental vitamin C… improved newborn pulmonary function results and decreased wheezing through 1 year in the offspring.”
2083 Whereas supplemental vitamin D for adults with asthma and lowish vitamin D levels did not reduce the rate of first treatment failure or exacerbation. One more for the heap of negative vitamin D intervention studies with non-bony outcomes.
2092 What would be your collective noun for a gathering of cardiologists? A Pontificate? An Oligarchy? A Pride? Few professional groups are so given to proclaiming their authority, especially when they can back it with evidence. But evidence changes, and this—fortunately— is sometimes reflected in the declarations of authority. In this study, the authors sought to characterize variations in the durability of class I (“procedure/treatment should be performed/administered”) American College of Cardiology/American Heart Association (ACC/AHA) guideline recommendations. Of 619 index recommendations, 495 (80.0%) were retained in the subsequent guideline version, 57 (9.2%) were downgraded or reversed, and 67 (10.8%) were omitted.
Lancet 31 May 2014 Vol 383
1889 The Lancet doesn’t seek to disguise the large contribution to its income that comes from sales of reprints to industry. But it would be nice if it could find some other business model. Here is the report of a trial funded by Forest Laboratories, one of whose employees designed the study, analysed data, and revised the manuscript. The eight week duration of the study was no doubt a factor in getting ethical approval to compare a fixed dose drug combination with placebo for newly diagnosed, uncomplicated high blood pressure. The drugs in the combination were nebivolol and valsartan. Believe it or not, they lowered blood pressure. So now (look, it says so in this paper from the Lancet) we can use the Forest combination as first line for newly diagnosed hypertension, instead of the cheaper and more rational alternatives.
1899 So what is this thing called “hypertension”? I got interested in this question about 20 years ago, especially in the context of progression to heart failure without systolic dysfunction, which unfortunately gets little space in this article. Putting behind the eight week trial just mentioned, we can pore over data here describing the lifetime course of this bundle of risk factors—made up of diastolic BP, systolic BP, pulse pressure, and BP variance, plus the effects of treatments. I’m afraid there is no way of summarising this wealth of information, except to quote the authors themselves: “The widely held assumptions that blood pressure has strong associations with the occurrence of all cardiovascular diseases across a wide age range, and that diastolic and systolic associations are concordant, are not supported by the findings of this high-resolution study. Despite modern treatments, the lifetime burden of hypertension is substantial. These findings emphasise the need for new blood pressure-lowering strategies, and will help to inform the design of randomised trials to assess them.”
1912 English general practice is doing well at controlling high blood pressure. Call it hypertension if you will, but it is just a subset of cardiovascular risk factors, according to age, specific variables, and everything else that’s dealt with in the preceding paper. And individuals should make their own treatment choices for themselves, taking into account all their other risk factors, but that is still well into the future. This study looked at the years between 1994 and 2011 in samplings which included BP measurement. There has been a steady rise in the detection of high blood pressure (defined as >140/90) and in the effectiveness of treatment, without any evidence of a sudden change after 2004, when payment by results (QOF) was introduced. And I am pleased to note that only 37% of people who fall within this overtight definition have their BP brought below those levels: this probably represents a good balance between the benefits and harms of treatment.
The BMJ 31 May 2014 Vol 348
Nobody has complained directly to me that I spend too much time talking about trial methodology, but I have a nagging fear that I might lose the attention of some of my clinician readers if I go into detail. Yet consider it from the patient’s point of view. You agree to be take part in a surgical trial. You know you will be randomized to a placebo or a procedure, and the placebo would actually mean having something done to you, like having a general anaesthetic and a wound but no operation, or the surgeon putting in a laparoscope and then doing nothing. If I had gone through that, I would want to be sure that the trial was really well reported, in such a way that everybody doing the operation would be able to know the results in detail. Indeed, I would like to see the results myself. So methodology and reporting really matter. Too many new surgical procedures still come and go on waves of fashion. Here’s a systematic review of the use of “placebos” in the evaluation of surgery. It shows that placebo arms are critical for proper evaluation of new or indeed old procedures: but also, alas, it shows that standards of reporting are terribly variable.
It’s just over two years since I had my first (and life changing) meeting with Glyn Elwyn, leading researcher of shared decision making, and one of the authors of a great little article called “Power Imbalance Prevents Shared Decision Making.” This is a wonderful discussion of how patients can collude in trying to do what they perceive that the doctor wants them to do. And of course doctors are often all too willing to collude in believing they have given the patient a free choice of options. The culture change which will embed true shared decision making in the whole of medicine is only just beginning. I would say, echoing Peabody’s famous dictum about patient care, that the secret of good shared decision making is wanting to share the decision. And although this applies above all to clinicians—as they wield the power in the encounter—it also applies to patients.
Plant of the Week: Decumaria sinensis
These are the best and most beautiful weeks of the garden year, where scents and sights combine to ravish. If you have small gardens, like ours, it is necessary to make your walls and fences count along with the rest. There are plenty of scented climbers, but none so useful and easy as Decumaria sinensis.
I’ve written about this plant before and it is a mystery that it remains a rarity. Is nobody listening to me? Here is an evergreen self-clinger with handsome leaves that is a pleasure to look at all the year round. It comes away easily if you need to stop it invading your gutters: which will happen, as once established it will grow to 10m or more. In the spring, it will be covered in foamy tufts of flower-head which will eventually open creamy white, and produce a wall of scent, like orange and elderflower mixed with honey.
If you have a decent sized bit of fence or wall, go in search of this lovely thing which will be an abundant source of pleasure every year. Unfortunately you may have to do a bit of hunting.